A detailed functional immune map of biologic-naïve active AS is provided, offering novel mechanistic insights and identifying candidate biomarkers for precision intervention.
Abstract
Ankylosing spondylitis (AS) is a chronic, immune-mediated inflammatory disorder primarily affecting the axial skeleton. It is characterized by bony fusion and syndesmophyte formation of the spine, leading to compromised mobility, reduced quality of life and increased mortality. However, the underlying immune dysregulation in AS remains poorly understood. We comprehensively profiled the peripheral immune landscape of 30 patients with active AS, all of whom were TNF-α blocker-naïve, capturing the immune profile during the active disease phase without biologic interference. Using advanced 11-color flow cytometry and FlowSOM clustering, 584 immunophenotypes were analyzed in AS and 30 age-and sex-matched healthy controls, with emphasis on both cellular composition and functional characteristics. AS patients displayed a distinctive functional “activated-exhausted” immune phenotype, dominated by CD4
+
CD28
+
CD38
+
PD-1
+
T cells and HLA-DR
+
CD38
+
CD4
−
CD8
−
double-negative (DN) T cells. DN T cells were significantly enriched in HLA-B27-positive patients, suggesting potential as a biomarker. Network analysis revealed seven central immune subsets associated with active disease, while functional assessment demonstrated impaired CD95
+
CD8
+
T cell apoptosis and disrupted B-cell maturation. These findings provide a detailed functional immune map of biologic-naïve active AS, offering novel mechanistic insights and identifying candidate biomarkers for precision intervention.
A divergent regulation of CD29 and CD49b integrins associated with HLA-B27 status in Iraqi AS patients is suggested and longitudinal validation is required to confirm their clinical utility as diagnostic or therapeutic targets.
Ahmed Ali Alshammari, M. Mohsin· Iranian Journal of Pathology· 0 citations
Pediatric immune thrombocytopenia (ITP) is an autoimmune cytopenia characterized by immune-mediated platelet destruction and impaired thrombopoiesis. Mucosa-associated invariant T (MAIT) cells are innate-like T cells activated by MR1-presented microbial metabolites and inflammatory cytokines, but their role in pediatric ITP and their relationship to eltrombopag therapy remain unclear. We analyzed peripheral blood mononuclear cells from healthy controls (n = 20), untreated pediatric ITP patients (n = 60), and eltrombopag-treated patients (n = 16). MAIT cells were quantified using MR1-5-OP-RU tetramers and surrogate gating (CD3+Vα7.2+CD161+). MAIT subsets, memory phenotype, chemokine receptor expression (CXCR3, CXCR5, CCR6), HLA-DR, intracellular cytokines (IFN-γ, TNF-α, IL-17 A, IL-22), and MR1+CD3- cells were analyzed by flow cytometry. Tetramer-defined MAIT cells were reduced in absolute number in pediatric ITP, including eltrombopag-treated patients, most prominently within the CD8+ subset, whereas their frequency among CD3+ T cells did not differ between untreated and eltrombopag-treated groups. In contrast, CD3+Vα7.2+CD161+ cells increased in untreated ITP and were lower in eltrombopag-treated patients. Untreated ITP patients exhibited reduced frequencies of IFN-γ- and TNF-α-producing MAIT cells, accompanied by increased IL-17-producing cells and TNF-α signal intensity. Conventional αβ T cells were reduced, whereas γδ T cells were increased; eltrombopag-treated patients exhibited γδ T-cell frequencies and cytokine-positive fractions closer to those of healthy controls. MR1+CD3- cells were expanded and displayed reduced HLA-DR expression in untreated ITP, whereas eltrombopag-treated patients showed lower MR1+CD3- frequencies and HLA-DR levels closer to healthy controls. These findings demonstrate coordinated alterations of the MAIT/MR1 axis and unconventional T-cell compartments in pediatric ITP and identify immunophenotypic differences associated with eltrombopag treatment.
Ekrem Ünal, Z. B. Azizoğlu, Metin Çil et al.· International Immunopharmaco...· 0 citations
Background: Ankylosing spondylitis (AS) associated with Crohn’s disease (CD) is a nosological form of spondyloarthropathies with a low population prevalence. The pathogenesis of this disease is not fully understood, and there are no precise differential diagnostic methods to distinguish AS associated with CD from AS and CD separately in the early stages of the disease. The main objective for this study is to define lymphocyte-mediated immunity in patients with AS associated with CD. Methods: For the pilot study, we recruited four groups: CD (n = 16), AS+CD (n = 13), AS (n = 13) and healthy controls (HC, n = 26). Immune phenotyping of peripheral blood lymphocytes was carried out via flow cytometry. Results: In the AS+CD group, circulating regulatory T-cell (Treg) levels were increased compared to the other groups. The frequency of CD73+ Tregs within the effector memory (EM) compartment was also elevated in the AS+CD group relative to the AS and CD groups alone. At the same time, the EM Tcyt and EM Th populations were lower in the AS+CD group compared to the CD group. Tfh17 levels were lower in the AS+CD group than in the AS group and showed a positive correlation with Bm5 and ‘switched’ memory B cells. Additionally, Tfh17 and ‘switched’ memory B cells correlated negatively with acute-phase markers, whereas Tfh2 correlated positively with the BASDAI activity index. Conclusions: In patients with AS associated with CD, exhaustion of the regulatory compartment of adaptive immunity is seen, whereas the humoral component appears oriented towards resolving the inflammatory responses.
A. Rubinstein, A. Aquino, D. Davydov et al.· Cells· 0 citations
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with poorly understood and complex pathophysiology with interplay between many immune and stromal cells. While the T cell infiltrate in HS is well-documented, the relationship between systemic memory T cells and those within the cutaneous microenvironment has yet to be fully elucidated. We performed a comparative analysis of skin and peripheral blood mononuclear cells (PBMCs) samples from HS patients and healthy controls using flow cytometry to evaluate T cell subsets and their cytokine profile with focus on TNF-α, IFN-γ, IL-17A. Within the memory compartment, CD4+ central memory T cells (TCM) were profoundly expanded in HS lesions (21%) compared to healthy skin (<1%). A positive correlation was observed between the levels of skin-infiltrating TCM and those found in the systemic circulation. Conversely, CD4+ resident memory T cells (TRM) were significantly depleted in HS lesions (~30% to <10%). Functional assays revealed a marked discordance between tissues; skin-derived memory cells exhibited a hyper-responsive phenotype, producing significantly higher levels of TNF-α, IFN-γ, and IL-17A than matched PBMCs. These data suggest that HS is characterized by a synchronized peripheral-lesional axis of CD4+ TCM cells. The TRM deficit may reflect phenotypic plasticity or retrograde migration during chronic inflammation. Crucially, the HS microenvironment appears to reprogram recruited memory cells, leading to a tissue-specific functional activation not reflected in the systemic circulation.
L. Casals‐Diaz, J. Romaní, A. Ezzaanouni et al.· Frontiers in Immunology· 0 citations
Pre-biologic STK17B expression was higher among patients who were later identified as non-responders to IL-17i compared with responders, suggesting that DRAK2 upregulation contributes to axSpA-related inflammation and to treatment resistance, warranting further mechanistic investigation.
P. Remalante-Rayco, S. Jo, Addison Pacheco et al.· Journal of Rheumatology· 0 citations
OBJECTIVE
Systemic sclerosis (SSc) is characterized by immune dysregulation and fibrosis. We investigated whether abatacept modulates CD319/SLAMF7-expressing cytotoxic T cells implicated in diffuse cutaneous SSc.
METHODS
In this ancillary ASSET trial analysis, PBMCs from 67 participants were analyzed at baseline and months 1, 3, and 6. Flow cytometry quantified CD4+CD319+ and CD8+CD319+ T cells, cytotoxic/activation markers, and stimulated intracellular IL-4, IL-17A, and IFN-γ. Analyses compared abatacept-treated molecular endotypes with placebo and related immune changes to modified Rodnan skin score (mRSS) change. Skin single-cell RNA sequencing included 5 healthy controls and 8 SSc patients.
RESULTS
At baseline, CD319+ T cells showed greater cytokine production, activation, and granzyme/perforin expression than CD319- T cells in 60 evaluable participants (p<0.001 to p<0.0001). Abatacept reduced CD4+CD319+ and CD8+CD319+ T cell frequencies at month 6; placebo did not. Effects were strongest in fibroproliferative patients, where CD8+CD319+ T cells decreased versus placebo (n=7 versus n=36; p=0.0377). In this endotype, abatacept reduced IL-4 in CD4+CD319+ and CD8+CD319+ T cells at month 3 (p=0.0468 and p=0.0287) and IL-17A in CD8+CD319+ T cells at month 6 (p=0.0004), while IFN-γ was unchanged. Reduction in CD4+CD319+ T cells correlated with mRSS improvement in abatacept-treated patients (r=0.5297, p=0.0423). Skin single-cell RNA-sequencing showed increased SLAMF7 expression in SSc T cells (p=0.017), enriched within cytotoxic subsets.
CONCLUSION
CD319+ T cells represent highly differentiated, activated cytotoxic effector populations in SSc. Abatacept selectively modulates these cells and suppresses associated pro-fibrotic and pro-inflammatory cytokines, particularly in the fibroproliferative subtype, where CD319+ T cell reductions correlate with clinical improvement.
Mikel Gurrea-Rubio, Laura A. Cooney, Kohei Maeda et al.· Arthritis & Rheumatology· 0 citations
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